title: Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460): coapplication of structure-based design and rapid multiple analogue synthesis on solid support.
abstract: Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2-P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)-prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 micrograms/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Brady
authors.forename: K J
authors.initials: KJ
authors.lastname: Stauffer
authors.forename: W C
authors.initials: WC
authors.lastname: Lumma
authors.forename: G M
authors.initials: GM
authors.lastname: Smith
authors.forename: H G
authors.initials: HG
authors.lastname: Ramjit
authors.forename: S D
authors.initials: SD
authors.lastname: Lewis
authors.forename: B J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: S J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: E A
authors.initials: EA
authors.lastname: Lyle
authors.forename: S D
authors.initials: SD
authors.lastname: Appleby
authors.forename: J J
authors.initials: JJ
authors.lastname: Cook
authors.forename: M A
authors.initials: MA
authors.lastname: Holahan
authors.forename: M T
authors.initials: MT
authors.lastname: Stranieri
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Vastag
authors.forename: A M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004285:Dogs; D015195:Drug Design; D000882:Haplorhini; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000991:Antithrombins; C110510:N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide; D011759:Pyrrolidines